Glomerulonephritis and small vessel vasculitis caused by antl-neutrophil cytoplasmic autoantibodies (ANCA) is the most common cause for rapidly progressive glomerulonephritis, which frequently leads to end stage renal disease If not diagnosed quickly and treated appropriately. This Project will use mouse models that closely resemble human ANCA disease to advance understanding of the pathogenesis of this autoimmune inflammatory process with the goal of translating this knowledge Into better treatment of patients. Specific Aim1 will Investigate the role of complement activation and Fcy receptor engagement in mediating ANCA disease. Complement studies will include evaluation of the effects of a novel small molecule inhibitor of human C5a receptor in mice genetically engineered to express human C5a receptor. Involvement of both activating Fcy receptors In Inducing Inflammation, as well as inhibitory Fcy receptors In modulating inflammation will be studies. Specific Aim 2 seeks to create models of ANCA disease directed at additional autoantigens to more closely parallel human disease. The current model is induced by antibodies to myeloperoxidase. This Aim will pursue models induced by antibodies to proteinase 3 and lysosomal membrane protein-2; and also will test the ability of complementary (anti-sense) peptides to induce pathogenic autoantibody responses to sense peptides. Specific Aim 3 will probe the genetic basis for variations in ANCA disease between different strains of mice, which mimics the marked variations in ANCA disease among patients. These studies will utilize a robust new method for genetic research in mice, the Collaborative Cross, which will illustrate the power of this approach for studying kidney diseases. Genes (and their protein products) that are found to influence disease in this animal model will be likely candidates for markers of disease activity and outcome in patients, and might also be logical targets for novel therapies. Investigation of inflammatory and immunologic processes in this animal model will provide insights into other renal and nonrenal inflammatory and autoimmune diseases. The goal of the research is to translate new knowledge from this model into improved outcomes for patients with this aggressive form of kidney disease.